Mean Daily Pain Score Research Articles

A pRospective, historical-controlled Evaluation of oLIceridine for moderate or sEVEre pain in patients with acute burn injuries (RELIEVE)

Oliceridine, a biased, selective opioid agonist, has shown a 3-fold preferential activation of the G-protein (i.e., analgesia) over β-arrestin pathway. β-arrestin activation is believed to be associated with higher adverse events, such as constipation, respiratory depression, and desensitization. There is no literature of use in patients with burn injuries. We hypothesized the use of oliceridine would provide adequate and safe analgesia after acute burn injury. Ten patients received oliceridine as their sole opioid for up to 7 days, which was compared to a random, historical cohort receiving standard of care (i.e, fentanyl, oxycodone, hydromorphone, and morphine). The historical control group was initially matched 2:1 (though 2 patients were ultimately excluded) with the oliceridine group according to age, percent total body surface area burned (TBSA), and number of operations. No patient had a history of known opioid, cocaine, or methamphetamine use, as this was an exclusion criterion for the prospectively-enrolled group. Baseline numerical rating scale (NRS) was similar for both groups [9 (7.8, 10) vs 9.5 (8.8, 10); p = 0.360). Over the 7-day period, mean daily pain scores significantly decreased in both groups. However, use of oliceridine was associated with a significantly larger decrease in mean pain score [-0.74 (-1.36, -0.12), p = 0.0215]. There was no difference in average daily morphine milligram equivalents (MME) [-14.02 (-67.22, 39.19), p = 0.5939]. There were no unexpected adverse events related to oliceridine. Oliceridine demonstrated significant pain relief, which was maintained over the 7-day study period. The control group demonstrated initial relief, but was not maintained despite similar MME.

545 A PRospective, Case-controlled Evaluation of oLIceridine for Moderate or sEVEre Pain After Burn Injury. (RELIEVE)

Abstract Introduction After acute burn injury, injured tissue and adjacent non-burned tissue, upregulate response to painful and non-painful stimulus (hyperalgesia and allodynia, respectively). Currently, high-dose fentanyl, oxycodone, hydromorphone, and morphine are used at profound doses to mitigate pain. Oliceridine (OLI), a biased, selective opioid agonist, has shown a 3-fold preferential activation of the G-protein (i.e., analgesia) over β-arrestin pathway. There is no literature of use in patients with burn injuries. We hypothesized the use of OLI would provide adequate and safe analgesia after acute burn injury. Methods This single-center, prospective, case-controlled trial was dual IRB approved and included patients with burn injuries admitted between April and September 2023. Informed consent was obtained from the 10 patients receiving OLI. OLI was the only allowed analgesic except for acetaminophen. Dosing and assessments were followed per study protocol and safety and efficacy assessed per study team daily at a minimum. The historical control (CTL) group (i.e., fentanyl, oxycodone, hydromorphone, morphine, etc) was matched 2:1 with the prospective OLI group. The CTL were screened in reverse chronology to find comparable groups according to age, % total body surface area burned (TBSA), history of opioid and illicit drug use, and number of operations. SAS 9.4 was used for descriptive statistics and modelling via UNIVARIATE and GLM procedures. Results Two CTL patients were excluded in the final analysis due to missing assessments. The OLI (n = 10) and CTL (n = 18) groups were comparable in age (52.3 ± 12.3 vs 63.1 ± 17.3 years, p = 0.228), TBSA [8 (3.3, 11.2) vs 6 (2.6, 9.3) percent], operations (0.5 per patient for both), and burn mechanism. No patient had a known history of opioid, cocaine, or methamphetamine use. The baseline Numeric Pain Rating Scale (NRS) for OLI and CTL were similar [9 (7.8, 10) vs 9.5 (8.8, 10); p = 0.360); however, the first day’s mean pain score was higher for CTL (4.8 vs. 5.9, p = 0.035). Over the 7-day period, mean daily pain scores significantly declined in patients receiving OLI (-2.65, p = 0.010), but not for CTL (+0.69, p = 0.496). Whereas, opioid usage [i.e., oral morphine milligram equivalents (MME)] was not significantly different across groups (p = 0.689) or days (p = 0.684). Total MME averaged per patient day were 65.2 and 69.6 mg/day in the OLI and control groups, respectively (P = 0.688). There were no unexpected adverse events related to OLI. Conclusions Although this sample of 10 patients limits inferences outside of acute burn injuries less than 20% TBSA, OLI demonstrated significant pain relief, which was maintained over the 7 days study period. Importantly, the control group demonstrated initial relief, but was not maintained, despite similar MME. Applicability of Research to Practice Oliceridine offers an effective solution for analgesia in patients with acute burn injury.

Evaluation of pain associated with the application of burn dressings.

Topical wound care after burn injury has revolutionized burn care. Dressings and topical solutions provide broad-spectrum antimicrobial coverage to prevent wound infection, be easy to apply and remove, and promote wound healing. A wide variety of dressings are available for providers to choose from based on wound characteristics. An additional factor to consider when making that decision is any pain associated with applying the dressing and frequency of dressing changes. This retrospective study aimed to examine the daily and maximum pain reported by patients and daily opioid consumption to determine if there are any differences among commonly used dressings including 5% sulfamylon solution (SMS), manuka honey, negative-pressure wound therapy (NPWT), silver sulfadiazine, and silver nylon. This study demonstrated that silver sulfadiazine had lower mean daily pain scores compared only to manuka honey as well as lower maximum scores when compared to all other dressings except silver nylon. Furthermore, the choice of dressing did not have an overwhelming effect on the amount of opioids consumed by patients during their hospital stay with manuka honey having less opioid consumption when compared to only 5% SMS and NPWT only. Further studies are needed with additional validated pain assessment tools and clinically relevant endpoints to fully elucidate the impact of burn dressings and other topical wound care options on pain.

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial

Dose-response relationship between epidural bupivacaine dose and mortality risk after surgical resection of nonsmall-cell lung cancer.

Preclinical studies have shown that local anesthetics may modify the growth and invasion of cancer cells. However, few clinical studies have evaluated their impact on cancer outcomes after tumor resection. In this single-center cohort study, patients who underwent surgical resection of stage IA through IIIB nonsmall-cell lung cancer and used patient-controlled epidural analgesia from 2005 to 2015 were recruited and followed until May 2017. Data of the epidural bupivacaine dose for each patient were obtained from infusion pump machines. Proportional hazards regression models were used to analyze the associations between bupivacaine dose with postoperative cancer recurrence and all-cause mortality. A total of 464 patients were analyzed. Among these patients, the mean bupivacaine dose was 352 mg (± standard deviation 74 mg). After adjusting for important clinical and pathological covariates, a significant dose-response relationship was observed between epidural bupivacaine dose and all-cause mortality (adjusted hazard ratio: 1.008, 95% confidence interval: 1.001-1.016, p = 0.029). The association between bupivacaine dose and cancer recurrence were not significant (adjusted hazard ratio: 1.000, 95% confidence interval: 0.997-1.002, p = 0.771). Age, sex, body mass index, mean daily maximum pain score, and pathological perineural infiltration were independently associated with bupivacaine dose. A dose-dependent association was found between epidural bupivacaine dose and long-term mortality among patients following surgical resection of nonsmall-cell lung cancer. Our findings do not support the hypothetical anticancer benefits of local anesthetics. More studies are needed to elucidate the role of local anesthetics in cancer treatment.

Patient-controlled analgesia and oral mucositis pain in hematological malignancies.

Oral mucositis (OM) pain is an anticipated complication of immunosuppressive therapies for hematological malignancies. Opioids are effective for OM-associated pain and dysfunction that is refractory to simple measures. At the study institution, parenteral opioids are preferentially prescribed for the treatment of complicated OM. This audit explores the efficacy of opioids for the management of OM pain using morphine, oxycodone, and fentanyl patient-controlled analgesia (PCA). Pain scores, opioid consumption, resumption of oral intake, and the duration of admission were retrospectively analyzed from patient records over an 18-month period. Two-thirds of included patients had ceased PCA therapy by day 6, by which time there was a meaningful 35.4 percent reduction in pain scores, with very few side effects reported. Interagent comparison demonstrated no significant differences in mean daily pain scores; however, a larger sample size would facilitate an investigation of clinically significant nuances in treatment differences, if they exist.

Open-Label Placebo in Children With Abdominal Pain or IBS

Source: Nurko S, Saps M, Kossovsky J, et al. Effect of Open-label placebo on children and adolescents with functional abdominal pain or irritable bowel syndrome: a randomized clinical trial [published online ahead of print January 31, 2022]. JAMA Pediatr. doi:10.1001/jamapediatrics.2021.5750Investigators from multiple institutions conducted a prospective crossover randomized trial to assess the effectiveness of open label placebo (OLP), ie, honestly prescribed placebo, in reducing pain in youths with functional abdominal pain or irritable bowel syndrome (IBS). Study participants were children 8-18 years old, with either functional abdominal pain or IBS, defined by Rome III criteria, who were enrolled at 3 children’s hospitals in the US between 2015 and 2018. During a 7-day observation period, study patients assessed their pain daily using a 0 to 100 mm visual analogue scale. Following the observation period, those with a mean daily pain scale of 25 mm were randomized to either OLP for 3 weeks or the control period. After 3 weeks, each participant crossed over to the other treatment group. A standard script was used during clinical encounters, with an explanation of placebos provided when a study child began OLP treatment. OLP was an inert suspension containing 85% sucrose, citric acid, water, and methyl paraben as a preservative, and patients were instructed to take 1.5 mL twice daily. Participants were allowed to take hyoscyamine dissolvable tablets as needed as a rescue pain medication. During the 6-week treatment period, study children recorded their daily pain using the visual analogue scale, which was the primary outcome. Differences in mean daily pain scores when participants were taking OLP or in the control period were compared using repeated-measures analysis of covariance; the model included mean pain score during the observation period and accounted for order of treatment. The main secondary outcome was number of hyoscyamine tablets used, with use during the OLP or control periods compared with a t-test.Data were analyzed on 30 patients, including 16 (53.3%) with functional abdominal pain and 14 (46.7%) with IBS. The mean age of study participants was 14.1 ±3.4 years, and 80% were female; the mean daily pain score in these youths during the 7-day observation period was 45.8 ±2.8 mm. Mean daily pain scores in study participants were 39.9 ±18.9 mm during the OLP period and 45.0 ±14.7 mm during the control period (difference, 5.2 mm; 95% CI, 0.2, 10.1; P = 0.03). Overall, 21 (70%) patients had higher daily pain scores during the control period than during the OLP period. Participants also took significantly more hysocyamine tablets during the control period than while receiving OLP (mean, 3.8 ±5.1 and 2.0 ±3.0 tablets, respectively; P = 0.001).The authors conclude that youths with functional abdominal pain or IBS experienced less pain during the OLP period than during the control period.Dr Rosenthal has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Disorders of gut-brain interaction such as functional abdominal pain and IBS often are chronic and difficult to treat due to a lack of identified organic targets.1 These disorders often are characterized by disabling symptoms, a poor quality of life, and high use of health care resources.2 In several double-blind studies of medications in children with these disorders, a high rate of favorable response among those receiving placebo has been observed.3 Due to ethical concerns about patient deception, the use of deceptive placebos as only treatments largely has been discouraged. However, recent data in adults suggest that use of OLP can achieve positive results.4In the current study, the authors utilizing OLP were able to significantly reduce pain in children and adolescents with disorders of gut-brain interaction as well as decrease their use of rescue medication. They concluded that OLP may provide an ethical way to harness the placebo effect as a therapeutic tool in the clinic. This is the first study in children that confirms the findings in adults suggesting that OLP can be used without compromising the therapeutic effect.There were several limitations to the current study; these included bias with a lack of treatment blinding, non-conscious expectations (the children’s desire to please the researchers), and the crossover design potentially contributing to carryover effects since the study lacked a washout period in which no “active treatment” was being used, and a short follow-up period.How can the current study results be explained? The exact nature of the response is still not known, but understanding the process and the mechanism behind the positive response may allow its use in routine clinical care in the future. Importantly, a non-pharmacologic therapy shows promise in treating functional abdominal pain and IBS.An OLP may reduce pain in children and adolescents with functional abdominal pain and IBS. (See AAP Grand Rounds. 2017[4]:43.)5

Effect of Open-label Placebo on Children and Adolescents With Functional Abdominal Pain or Irritable Bowel Syndrome

Although it is widely believed that concealment or deception is required to elicit a placebo response, recent studies with adults suggest that open-label placebo (OLP) (ie, honestly prescribed placebos) can yield significant benefits. No studies of OLP have been performed with children. To evaluate the efficacy of OLP for the treatment of children and adolescents with functional abdominal pain or irritable bowel syndrome. This multicenter crossover randomized clinical trial was conducted from July 1, 2015, to June 15, 2018, at 3 US centers among children and adolescents aged 8 to 18 years with functional abdominal pain or irritable bowel syndrome defined per Rome III criteria. Statistical analysis was performed from March 1, 2019, to September 30, 2020, on an intention-to-treat basis. Patients completed 1 week of observation prior to randomization to 1 of 2 counterbalanced groups: OLP for 3 weeks followed by a 3-week control period or control period for 3 weeks followed by OLP for 3 weeks. During the OLP period, participants took 1.5 mL of an inert liquid placebo twice a day. A standardized method for explaining the OLP was used, and the interaction with clinicians had the same duration and style for both time periods. Hyoscyamine was allowed as a rescue medication. The primary outcome was the mean daily pain score during each of the interventions, measured on a 0- to 100-mm visual analog scale, where higher scores indicated greater pain. The number of rescue medications taken during each intervention served as an objective secondary measure. Thirty patients (mean [SD] age, 14.1 [3.4] years; 24 female participants [80.0%]; 16 [53.3%] with functional abdominal pain and 14 [46.7%] with irritable bowel syndrome) completed the study. The mean (SD) pain scores were significantly lower during OLP treatment compared with the control period (39.9 [18.9] vs 45.0 [14.7]; difference, 5.2; 95% CI, 0.2-10.1; P = .03). Patients took nearly twice as many hyoscyamine pills during the control period compared with during the OLP period (mean [SD] number, 3.8 [5.1] pills vs 2.0 [3.0] pills; difference, 1.8 pills; 95% CI, 0.5-3.1 pills). During OLP, patients with functional abdominal pain or irritable bowel syndrome reported significantly less pain and took significantly fewer pain medications. Open-label placebo may be an effective treatment for children and adolescents with functional abdominal pain or irritable bowel syndrome. ClinicalTrials.gov Identifier: NCT02389998.

Intercostal liposomal bupivacaine injection for rib fractures: A prospective randomized controlled trial.

Blunt chest wall injury accounts for 15% of trauma admissions. Previous studies have shown that the number of rib fractures predicts inpatient opioid requirements, raising concerns for pharmacologic consequences, including hypotension, delirium, and opioid dependence. We hypothesized that intercostal injection of liposomal bupivacaine would reduce analgesia needs and improve spirometry metrics in trauma patients with rib fractures. A prospective, double-blinded, randomized placebo-control study was conducted at a Level I trauma center as a Food and Drug Administration investigational new drug study. Enrollment criteria included patients 18 years or older admitted to the intensive care unit with blunt chest wall trauma who could not achieve greater than 50% goal inspiratory capacity. Patients were randomized to liposomal bupivacaine or saline injections in up to six intercostal spaces. Primary outcome was to examine pain scores and breakthrough pain medications for 96-hour duration. The secondary endpoint was to evaluate the effects of analgesia on pulmonary physiology. One hundred patients were enrolled, 50 per cohort, with similar demographics (Injury Severity Score, 17.9 bupivacaine 17.6 control) and comorbidities. Enrolled patients had a mean age of 60.5 years, and 47% were female. Rib fracture number, distribution, and targets for injection were similar between groups. While both groups displayed a decrease in opioid use over time, there was no change in mean daily pain scores. The bupivacaine group achieved higher incentive spirometry volumes over Days 1 and 2 (1095 mL, 1063 mL bupivacaine vs. 900 mL, 866 mL control). Hospital and intensive care unit lengths of stay were similar and there were no differences in postinjection pneumonia, use of epidural catheters or adverse events bet ween groups. While intercostal liposomal bupivacaine injection is a safe method for rib fracture-related analgesia, it was not effective in reducing pain scores, opioid requirements, or hospital length of stay. Bupivacaine injection transiently improved incentive spirometry volumes, but without a reduction in the development of pneumonia. Therapeutic/care management, Level II.

The duration of mediastinal chest tube drainage is not associated with postoperative pain or opioid consumption after cardiac surgery

Objectives. Mediastinal chest tubes are considered to be a significant factor causing postoperative pain after cardiac surgery. The aim of the study was to ascertain whether the duration of mediastinal drainage is associated with postoperative pain and opioid consumption. Design. A total of 468 consecutive patients undergoing cardiac surgery at the Tampere University Hospital between December 2015 and August 2016 were retrospectively analyzed. The first 252 patients were treated according to short and the following 216 patients according to extended drainage protocol, in which the mediastinal chest tubes were habitually removed on the first and second postoperative day, respectively. The oxycodone hydrochloride consumption, as well as daily mean pain scores assessed by numeric/visual rating scales, were compared between the groups. Results. The mean daily pain scores and cumulative opioid consumption were similar in both groups. Patients with reduced ejection fraction, diabetes, and peripheral vascular disease reported lower initial pain scores. The median cumulative oxycodone hydrochloride consumption did not differ according to the drainage protocol but was higher in males, smokers, and after aortic surgery. In contrast, patients with advanced age, hypertension, and peripheral vascular disease had lower consumption. In multivariable analysis, male sex and aortic surgery were associated with higher and advanced age with lower opioid use. Conclusions. The length of mediastinal chest tube drainage is not associated with the amount of postoperative pain or need for opioids after cardiac surgery. Male sex and aortic surgery were associated with higher and advanced age with lower overall opioid consumption.

Magnesium for treating sickle cell disease.

Sickle cell disease is an autosomal recessive inherited haemoglobinopathy which causes painful vaso-occlusive crises due to sickle red blood cell dehydration. Vaso-occlusive crises are common painful events responsible for a variety of clinical complications; overall mortality is increased and life expectancy decreased compared to the general population. Experimental studies suggest that intravenous magnesium has proven to be well-tolerated in individuals hospitalised for the immediate relief of acute (sudden onset) painful crisis and has the potential to decrease the length of hospital stay. Some in vitro studies and open studies of long-term oral magnesium showed promising effect on pain relief but failed to show its efficacy. The studies show that oral magnesium therapy may prevent sickle red blood cell dehydration and prevent recurrent painful episodes. There is a need to access evidence for the impact of oral and intravenous magnesium effect on frequency of pain, length of hospital stay and quality of life. This is an updated version of the review. To evaluate the effects of short-term intravenous magnesium on the length of hospital stay and quality of life in children and adults with sickle cell disease. To determine the effects of long-term oral magnesium therapy on the frequency of painful crises and the quality of life in children and adults with sickle cell disease. We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 03 February 2019.Date of last search of other resources (clinical trials registries): 04 April 2019. We searched for published and unpublished randomized controlled studies of oral or intravenous magnesium compared to placebo or no magnesium. Authors independently assessed the study quality and extracted the data using standard Cochrane methodologies. We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Of these, two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies in this comparison, mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation.The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence).Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence). Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.

The Effects of Infiltration of Liposomal Bupivacaine for Pain Control After Cesarean Delivery: A Randomized Trial [19T

INTRODUCTION: In response to the growing opioid epidemic, we determine whether the addition of liposomal bupivacaine infiltration administered above and below the fascial layer and within the subcutaneous tissue at the time of closure post cesarean delivery would reduce pain scores compared to the use of intra-thecal morphine alone. METHODS: Randomized, placebo-controlled, single-blinded study. Eligible women over 17 years of age and at least 34 weeks gestation, non-emergent cesarean delivery under spinal anesthesia. Random assignment to receive either intrathecal Astramorph® and saline wound infiltration or intrathecal Astramorph® and wound infiltration with liposomal bupivacaine (Exparel®). Primary outcome was post-operative pain scores measured via visual analog scale until discharge. Secondary outcomes included side effects and patient satisfaction. A t-test was used to assess differences between groups for continuous variables, and a chi-square test was used to assess differences for categorical variables. Informed consent and IRB approval obtained. RESULTS: Of the 22 eligible subjects identified during the study interval, 18 were randomized and completed the study. The groups were similar in regards to demographic parameters. As compared to the placebo group, the mean daily pain scores were significantly lower in the Exparel® group on post-operative days 1 and 2 (P < 0.05) and required less opioids. No significant differences between groups in satisfaction scores or the presence of side effects. No patients required additional opioid analgesia after discharge. CONCLUSION: Wound infiltration with liposomal bupivacaine during cesarean delivery reduced post-operative pain scores without increasing side effects. Supports the effectiveness of this multimodal approach to post cesarean delivery analgesia.

Characterization of Abdominal Pain Response to Rifaximin in Patients with Irritable Bowel Syndrome with Diarrhea (IBS-D), by Baseline Pain Severity: Presidential Poster Award

Introduction: Rifaximin is indicated for the treatment of IBS-D in adults. This post hoc analysis of a phase 3 trial evaluated response to 2 courses of rifaximin in patients subgrouped by baseline abdominal pain severity. Methods: Adults with IBS-D (mean daily abdominal pain score ≥3) received a 2-week course of rifaximin 550 mg three times daily. Abdominal pain was assessed daily (score range, 0-10). Patients who responded (during 4-week evaluation period) and then had symptom recurrence during an additional ≤ 18-week observation period (up to 22 weeks post-treatment) received a second 2-week rifaximin course and response was assessed during a 4-week evaluation period. Response was defined as a ≥30% decrease from baseline in mean weekly abdominal pain score and ≥50% decrease from baseline in days/week with Bristol Stool Scale type 6/7 (mushy/watery) stool (composite endpoint) for ≥2 of the first 4 weeks post-treatment. Subgroups were defined by baseline abdominal pain scores of <5.0 (group A), ≥5.0 to <8.0 (group B), and ≥8.0 (group C). Results: 2579 patients received the first rifaximin course (68.2% female; mean age, 46.4 y; mean baseline abdominal pain score, 5.5 [median, 5.4]). In 2438 patients evaluable for efficacy (group A, n=962; group B, n=1260; group C, n=216), response to rifaximin (composite endpoint) was observed in 40.4%, 47.0%, and 43.1% of patients in groups A, B, and C, respectively. Response for the individual abdominal pain component was observed in 57.0%, 57.9%, and 49.5% of patients, respectively. In 328 patients who experienced symptom recurrence and received repeat treatment with rifaximin (group A, n=114; group B, n=178; group C, n=36), median baseline abdominal pain score at repeat treatment baseline was 4.4 (mean, 4.6), lower than observed at first-course baseline. When subgrouped by repeat treatment baseline pain score, response to repeat rifaximin treatment (composite endpoint) was reported in 38.6%, 34.8%, and 27.8% of patients in groups A, B, and C, respectively. Response for abdominal pain component was reported by 57.9%, 50.6%, and 50.0% of patients, respectively. Conclusion: In adults with IBS-D treated with rifaximin, a high percentage of patients had clinically meaningful improvement in abdominal pain irrespective of baseline abdominal pain severity category and treatment course (first vs repeat treatment). These data support rifaximin efficacy in improving IBS-related abdominal pain symptoms.

Split laminotomy versus conventional laminotomy: postoperative outcomes in pediatric patients.

OBJECTIVE Split laminotomy is a technique for accessing the spinal canal from the posterior midline that minimizes muscle dissection and bone removal. Benefits of this approach in minimizing postoperative pain and muscle atrophy in the adult population have been reported, but pediatric data are limited. Herein, the authors evaluate the benefits of the split laminotomy technique in pediatric patients. METHODS Data obtained in patients who underwent posterior spine surgery at Children's Hospital of Wisconsin for an intradural midline pathology between April 2008 and June 2015 were reviewed retrospectively. Each patient was assigned to one of two groups, the split-laminotomy or conventional-laminotomy group. The primary outcomes assessed were mean daily pain score, total opioid use over a period of 72 hours after surgery, and the degree of paraspinal muscle atrophy and fat infiltration found on short-term (1-4 months) and long-term (1-4 years) follow-up spine MRI studies. RESULTS A total of 117 patients underwent lumbar-level surgery (83 conventional laminotomy, 34 split laminotomy), and 8 patients underwent thoracic-level surgery (4 in each group). No significant difference in the mean daily pain scores between groups was found. The daily opioid use was significantly lower in the split-laminotomy group on postoperative day 0 (POD0) and POD1 but not on POD2 (p = 0.01, 0.01, and 0.10, respectively). The total opioid use over the 72-hour postoperative period was significantly lower in the split-laminotomy group (p = 0.0008). The fat/muscle ratio was significantly higher in both the short-term and long-term follow-up periods in the conventional-laminotomy group (p = 0.01 and 0.0002, respectively). The rate of change of paraspinal muscle fat infiltration was significantly lower in the split-laminotomy group than in the conventional-laminotomy group (p = 0.007). The incidence of complications was not significantly different between groups (p = 0.08). CONCLUSIONS This study was of the largest series reported thus far of pediatric patients who underwent split laminotomy and the only controlled study that has involved children. The authors' results reinforce the short-term benefit of split laminotomy in minimizing acute postoperative pain and long-term benefits of decreasing muscle atrophy and fatty degeneration, which are known to be associated with the development of chronic pain and spinal instability. Additional efforts for assessing long-term effects in the development of chronic pain, spinal instability, and spinal deformity are still necessary.

Magnesium for treating sickle cell disease.

Sickle cell disease is an autosomal recessive inherited haemoglobinopathy which causes painful vaso-occlusive crises due to sickle red blood cell dehydration. Vaso-occlusive crises are common painful events responsible for a variety of clinical complications; overall mortality is increased and life expectancy decreased compared to the general population. Experimental studies suggest that intravenous magnesium has proven to be well-tolerated in individuals hospitalised for the immediate relief of acute (sudden onset) painful crisis and has the potential to decrease the length of hospital stay. Some in vitro studies and open studies of long-term oral magnesium showed promising effect on pain relief but failed to show its efficacy. The studies show that oral magnesium therapy may prevent sickle red blood cell dehydration and prevent recurrent painful episodes. There is a need to access evidence for the impact of oral and intravenous magnesium effect on frequency of pain, length of hospital stay and quality of life. To evaluate the effects of short-term intravenous magnesium on the length of hospital stay and quality of life in children and adults with sickle cell disease. To determine the effects of long-term oral magnesium therapy on the frequency of painful crises and the quality of life in children and adults with sickle cell disease. We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 01 December 2016.Date of last search of other resources (clinical trials registries): 29 March 2017. We searched for published and unpublished randomized controlled studies of oral or intravenous magnesium compared to placebo or no magnesium. Authors independently assessed the study quality and extracted the data using standard Cochrane methodologies. We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies presenting this comparison mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation.The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence).Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence). Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.

Safety and Efficacy of a Topical Sodium Channel Inhibitor (TV-45070) in Patients With Postherpetic Neuralgia (PHN): A Randomized, Controlled, Proof-of-Concept, Crossover Study, With a Subgroup Analysis of the Nav1.7 R1150W Genotype.

Objective:The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism.Materials and Methods:This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks. The primary efficacy measure was the difference in change in mean daily pain score from baseline compared with the last week of placebo and active treatment. Secondary endpoints included responder rate analyses and a further exploratory analysis of response in carriers of the Nav1.7 R1150W polymorphism was conducted.Results:Seventy patients were enrolled and 54 completed the study. TV-45070 was safe and well tolerated. No statistical difference was observed between treatments for the primary endpoint. However, the proportion of patients with ≥50% reduction in mean pain scores at week 3 was greater on TV-45070 than on placebo (26.8% vs. 10.7%, P=0.0039). Similarly, a greater proportion of patients on TV-45070 had a ≥30% reduction in mean pain scores at week 3 (39.3% on TV-45070 vs. 23.2% on placebo, P=0.0784). Of note, 63% of patients with the R1150W polymorphism versus 35% of wild-type carriers had a ≥30% reduction in mean pain score on TV-45070 at week 3 (no inferential analysis performed).Conclusions:The 50% responder analysis suggests a subpopulation may exist with a more marked analgesic response to TV-45070.The trend toward a larger proportion of responders within Nav1.7 R1150W carriers warrants further investigation.

A Randomized Controlled Trial Comparing the Low FODMAP Diet vs. Modified NICE Guidelines in US Adults with IBS-D.

There has been an increasing interest in the role of fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) in irritable bowel syndrome (IBS). We report results from the first randomized controlled trial of the low FODMAP diet in US adults with IBS and diarrhea (IBS-D). The objectives were to compare the efficacy of the low FODMAP diet vs. a diet based upon modified National Institute for Health and Care Excellence guidelines (mNICE) on overall and individual symptoms in IBS-D patients. This was a single-center, randomized-controlled trial of adult patients with IBS-D (Rome III) which compared 2 diet interventions. After a 2-week screening period, eligible patients were randomized to a low FODMAP or mNICE diet for 4 weeks. The primary end point was the proportion of patients reporting adequate relief of IBS-D symptoms ≥50% of intervention weeks 3-4. Secondary outcomes included a composite end point which required response in both abdominal pain (≥30% reduction in mean daily pain score compared with baseline) and stool consistency (decrease in mean daily Bristol Stool Form of ≥1 compared with baseline), abdominal pain and stool consistency responders, and other key individual IBS symptoms assessed using daily questionnaires. After screening, 92 subjects (65 women, median age 42.6 years) were randomized. Eighty-four patients completed the study (45 low FODMAP, 39 mNICE). Baseline demographics, symptom severity, and nutrient intake were similar between groups. Fifty-two percent of the low FODMAP vs. 41% of the mNICE group reported adequate relief of their IBS-D symptoms (P=0.31). Though there was no significant difference in the proportion of composite end point responders (P=0.13), the low FODMAP diet resulted in a higher proportion of abdominal pain responders compared with the mNICE group (51% vs. 23%, P=0.008). Compared with baseline scores, the low FODMAP diet led to greater reductions in average daily scores of abdominal pain, bloating, consistency, frequency, and urgency than the mNICE diet. In this US trial, 40-50% of patients reported adequate relief of their IBS-D symptoms with the low FODMAP diet or a diet based on modified NICE guidelines. The low FODMAP diet led to significantly greater improvement in individual IBS symptoms, particularly pain and bloating, compared with the mNICE diet.

Randomized trial of epidural vs. subcutaneous catheters for managing pain after modified Nuss in adults.

Minimally invasive repair of pectus excavatum (MIRPE) is now performed in adults. Managing adult patients' pain postoperatively has been challenging due to increased chest wall rigidity and the pressure required for supporting the elevated sternum. The optimal pain management regimen has not been determined. We designed this prospective, randomized trial to compare postoperative pain management and outcomes between thoracic epidural analgesia (TEA) and bilateral subcutaneous infusion pump catheters (On-Q). Patients undergoing MIRPE (modified Nuss) underwent random assignment to TEA or On-Q group. Both groups received intravenous, patient-controlled opioid analgesia, with concomitant delivery of local anesthetic. Primary outcomes were length of stay (LOS), opioid use, and pain scores. Of 85 randomly assigned patients, 68 completed the study [52 men, 76.5%; mean (range) age, 32.2 (20.0-58.0) years; Haller index, 5.9 (range, 3.0-26.7)]. The groups were equally matched for preoperative variables; however, the On-Q arm had more patients (60.3%). No significant differences were found between groups in mean daily pain scores (P=0.52), morphine-equivalent opioid usage (P=0.28), or hospital stay 3.5 vs. 3.3 days (TEA vs. On-Q; P=0.55). Thirteen patients randomized to TEA refused the epidural and withdrew from the study because they perceived greater benefit of the On-Q system. Postoperative pain management in adults after MIRPE can be difficult. Both continuous local anesthetic delivery by TEA and On-Q catheters with concomitant, intravenous, patient-controlled anesthesia maintained acceptable analgesia with a reasonable LOS. In our cohort, there was preference for the On-Q system for pain management.

A Rapid Recovery Pathway for Adolescent Idiopathic Scoliosis That Improves Pain Control and Reduces Time to Inpatient Recovery After Posterior Spinal Fusion

Study DesignRetrospective comparative cohort. ObjectivesTo determine if a standardized multimodal analgesic and rehabilitation protocol (rapid recovery pathway [RRP]) in adolescent idiopathic scoliosis (AIS) patients undergoing posterior spinal fusion (PSF) could improve pain control, reduce opioid-related complications, and expedite early mobilization. BackgroundSeveral reports have described postoperative recovery pathways for AIS patients undergoing PSF that shorten length of stay (LOS) without reporting the impact such pathways might have on patients' pain or quality of recovery. MethodsWe compared two high-volume surgeons' patients managed on our conventional pathway (CP) or our RRP. The CP analgesia consisted of intraoperative methadone and postoperative patient-controlled analgesia (PCA) until tolerating oral analgesics, with adjunctive diazepam. Analgesia on the RRP includes intraoperative methadone and postoperative PCA; patients also receive preoperative gabapentin and acetaminophen, intraoperative intravenous acetaminophen, and postoperative diazepam, gabapentin, acetaminophen, and ketorolac. Ambulation and full diet are permitted beginning postoperative day 1. The primary outcome was mean daily pain scores. Secondary outcomes were LOS, time to pathway milestone completions, and frequency of opioid-related side effects requiring treatment. ResultsThere were 58 patients in the RRP group and 80 patients in the CP group. Patients on RRP had improved mean daily pain scores on postoperative days 0 (p = .027), 1 (p < .001) and 2 (p = .004). RRP patients were discharged home 31% earlier, discontinued from PCA 34% earlier and had their urinary catheters removed 26% earlier. Total opioid consumption decreased on postoperative day 0 (p < .001), but not postoperative day 1 (p = .773) or 2 (p = .343). Fewer patients on the RRP required medication for opioid-induced pruritus (p = .001), but there was no difference in the frequency of odansetron administration (p = .566). There were no differences in 30-day rates of readmission (p = .407). ConclusionImplementation of standardized RRP resulted in reduced pain, faster mobilization, reduced frequency of opioid-related side-effects, and earlier discharge.

Research in brief

In the first of a pair of randomised, double-blind, placebo-controlled trials published in The Lancet, investigators of the TESLA Part B study assessed the efficacy of the PCSK9 antibody, evolocumab, for homozygous familial hypercholesterolaemia. Patients received monthly evolocumab (n=33) or placebo (n=16) for 12 weeks. The percentage change in ultracentrifugation LDL cholesterol from baseline to week 12 was −23·1% (95% CI −30·7 to −15·4) in the intervention group compared with 7·9% (−2·7 to 18·5) in the placebo group (treatment difference −30·9%, −43·9 to −18·0; adjusted p<0·0001). In the second study, the RUTHERFORD-2 trialists allocated patients with heterozygous familial hypercholesterolaemia to evolocumab (n=110) or placebo (n=54) once every 2 weeks, or monthly evolocumab (n=110) or placebo (n=55), for 12 weeks. Both doses of the study drug led to reductions in LDL cholesterol from baseline to week 12 compared with placebo (treatment difference for once every 2 weeks dose −59·2% [95% CI −65·1 to −53·4] and for the monthly dose −61·3% [–69·0 to −53·6]; p<0·0001 for both). Treatment was generally well tolerated. The CALORIES trial investigators have attempted to resolve the uncertainty regarding the delivery route for early nutritional support in critical care. Their pragmatic, open, multicentre, randomised trial included patients with an unplanned admission to ICU who required early nutritional support. Parenteral or enteral nutrition was administered for up to 5 days. 30 day mortality was 33% (393/1188) in patients allocated to parenteral nutrition and 34% (409/1195) in patients allocated to enteral nutrition; the difference between the groups was not statistically significant (absolute difference between groups 1·15, 95% CI −2·65 to 4·94). Incidence of hypoglycaemia and vomiting was lower in the parenteral group than in the enteral group. A phase 2 randomised dose-ranging trial of mirogabalin has yielded some promising results for people with diabetes and painful peripheral neuropathy. Investigators allocated 452 patients with type 1 or type 2 diabetes and painful peripheral neuropathy to placebo, five different doses of mirogabalin, or pregabalin (active comparator) for 5 weeks. Higher mirogabalin doses (15 mg/day, 20 mg/day, and 30 mg/day) were associated with significantly greater reductions in mean daily pain score from baseline to week 5 compared with placebo (least squares mean difference −0·94, −0·88, and −1·01, respectively; p<0·05). The most common adverse events associated with mirogabalin treatment were dizziness and somnolence. The ADVANCE-ON collaborators report the post-trial observational follow-up of 8494 patients with type 2 diabetes who had participated in the ADVANCE factorial trial. In the ADVANCE trial, although the combination of perindopril and indapamide for blood pressure lowering over 4·5 years was associated with a reduction in mortality, intensive glycaemic control over 5 years was not. In ADVANCE-ON, after 5·9 years post-trial follow-up, reductions in cardiovascular mortality (hazard ratio 0·88, 95% CI 0·77 to 0·99) and all-cause mortality (0·91, 0·84 to 0·99) persisted for the active blood pressure lowering treatment group. There were no differences in cardiovascular mortality or all-cause mortality between the intensive glycaemic control or standard care cohorts after 5·4 years of post-trial follow-up. Liraglutide treatment could have effects beyond glycaemic control alone, suggest the investigators of the LIBRA placebo-controlled trial. Researchers randomly assigned patients with type 2 diabetes to 48 weeks of daily placebo injection (n=25) or subcutaneous liraglutide (n=26). In advance of receiving treatment, all patients had 4 weeks of short-term intensive insulin treatment to improve glucotoxicity caused by diabetes. At 48 weeks, patients in the liraglutide cohort had better pancreatic β-cell function than those in the placebo group, as assessed by the Insulin Secretion-Sensitivity Index-2 (mean [SE] baseline adjusted values: 339·8 [27·8] and 229·3 [28·4], respectively; p=0·008). However, the beneficial effect on β cells was not maintained following termination of liraglutide treatment. Results from a single-centre randomised controlled trial cast the spotlight on the role of vitamin D in intensive care. Investigators for the VITdAL-ICU trial allocated critically ill patients with vitamin D deficiency to receive a loading dose of vitamin D3 (540 000 IU) or placebo, and then five, monthly, maintenance doses. The primary outcome did not differ between groups assigned to vitamin D3 (n=237) or placebo (n=238), with patients receiving vitamin D3 staying in hospital for a median of 20·1 days (IQR 11·1–33·3), and placebo patients for 19·3 days (11·1–34·9; p=0·98). Length of ICU stay, in-hospital death, and death at 6 months did not significantly differ between the two groups.